The invention relates in general to the treatment of intestinal epithelial cell syndromes in humans characterized by reduced absorption of foodstuffs by intestinal cells. More particularly, the invention relates to stimulation of epithelial cell growth and function in the small intestine of patients requiring same by treatment with with Hepatocyte Growth Factor ("HGF").
The etiology of inadequate intestinal absorption includes: loss due to development abnormalities such as intestinal atresias and in utero midgut volvus; postnatal loss from surgical resection after infarction (midgut volvulus or vascular occlusion), trauma or tumor; inflammation, such as is due to infection (necrotizing enterocolitis and acute gastroenteritis) and autoimmune etiologies such as in Crohn's Disease and ulcerative colitis.
Many of the conditions result in "Short Bowel Syndrome" ("SBS"), the expression applied to syndromes that occur following extensive resection of the small intestine. The main consequence of SBS is malabsorption, which leads to malnutrition, dehydration, and potentially lethal metabolic alterations. The severity of the syndrome is determined by the length of functional small intestine remaining after resection. The adaptive response of the remaining intestine is the crucial factor in the subsequent quality of life of such patients. altered motility, resulting in increased luminal absorptive ability. However, this adaptive response is frequently insufficient to allow for sufficient enteral nutrition.
To better the quality of life of the aforementioned patients, it is essential to increase the capacity for absorption of the remaining small intestine. It follows, therefore, that there is an important need for agents to stimulate the functioning and numbers of the remaining epithelial cells lining the small intestine in such disorders.
Regeneration of the liver in experimental animals after partial hepatectomy or liver injury is believed to be due, at least in part, to the effects of HGF on hepatocytes. HGF is a heterodimeric, heparin-binding protein composed of heavy .alpha. and light .beta. chains of molecular weights of 70 kDa and 35 kDa, respectively, that is known to stimulate the growth, i.e., DNA synthesis, of hepatocytes in tissue culture. Matsumoto et al., Crit. Revs. Oncogen. 3: 27 (1992).
Recent studies have demonstrated that HGF stimulates the growth, not only of hepatocytes in culture, but also of intestinal crypt (IEC-6) epithelial cells in vitro. Dignass et al., Biochem. Biophys. Res. Commun. 202: 701 (1994). In addition, it has been demonstrated that the expression of HGF and HGF receptor (c-MET) genes can occur in the gastrointestinal tract, lung, kidney, brain, thymus and pancreas. Based on such studies, it has been speculated that HGF is a mesenchymal cell-derived growth factor that acts on epithelial cells through paracrine and endocrine mechanisms to achieve cell growth. Matsumoto et al. (1992), above.
Despite these speculations, it is not known whether HGF has cell growth and increased cell function effects on intestinal epithelial cells in vivo, that is, whether HGF, administered systemically or intraluminally to animals suffering from intestinal malabsorption due to reduced epithelial cell number and function, e.g., in SBS, would increase the numbers and functional activity of the epithelial cells of the remaining small intestine sufficient to reverse intestinal malabsorption in such subjects.
It is an object of this invention to use HGF in vivo to increase the functional (i.e., absorptive) capacity of small intestinal epithelial cells remaining following the institution of intestinal malabsorption as a result of mass reduction or functional reduction of a portion of the small bowel.